MAP 2017 – Molecular Analysis for Personalised Therapy

ESMO 2018 Congress

Preceptorship Courses

Apply now to join one of our Preceptorship courses on Immuno-oncology, Lung Cancer and Ovarian Cancer

Workshops & Courses

ESMO fosters the advancement of cancer research by supporting clinical trials workshops to inspire young oncologists from different disciplines across the globe to become the next generation of active researchers.

Patient Guides

Guides for Patients are designed to assist patients, their relatives and caregivers to better understand the nature of different types of cancer and evaluate the best available treatment choices

Personalised Medicine Explained

Video interviews and articles designed to help patients, policy makers and other non-medical professionals better understand the principles of personalised cancer medicine

Getting the Most out of Your Oncologist

Now available in Romanian, our Guide for Patients with Advanced Cancer is designed for patients, their family members and oncologists.

Designated Centres of Integrated Oncology and Palliative Care

The ESMO Designated Centres of Integrated Oncology and Palliative Care accreditation programme recognises cancer centres which provide comprehensive services in supportive and palliative care as part of their routine care.

Until regulatory withdrawal of bevacizumab/docetaxel in 2011, this combination was considered as a valid first-line option for HER2-negative metastaic breast cancer based on results of a phase III trial. The PFS and response rate (RR) with maximum 9 cycles of first-line docetaxel were significantly improved by adding bevacizumab continued until disease progression.

The open-label randomised phase III IMELDA trial tested whether switching to a more tolerable chemotherapy with a different mechanism of action while continuing VEGF inhibition may be more effective. It was meant that by adding capecitabine to maintenance bevacizumab continued until disease progression after initial bevacizumab/docetaxel will improve PFS. The study findings were presented by Dr Joseph Gligorov of the Medical Oncology Department, Tenon University Hospital, Paris, France.

The primary endpoint was PFS from randomisation to progression/death; secondary endpoints included RR, clinical benefit rate, time to disease progression, OS from randomisation, safety and quality of life. The sample size was calculated based on a PFS hazard ratio (HR) of 0.70 with median PFS improvement from 5.8 to 8.3 months. In total 360 enrolled patients were required for 290 randomised patients. It was planned that 244 PFS events provide 80% power at 5% 2-sided alpha. The study was not designed for formal OS comparison.

Between June 2009 and March 2011 when enrolment was prematurely terminated, 287 patients were enrolled and 284 of them treated with 185 (65%) who completed initial treatment and subsequently randomised to maintenance treatment. The pprotocol was amended to continue follow-up for 2 years after last randomisation.

Median age in the bevacizumab arm was 54 years and 49 years in the bevacizumab/capecitabine arm. Triple-negative disease was recorded in 22% of patients included in the bevacizumab arm and 27% of patients in the bevacizumab/capecitabine arm. Visceral metastases were nearly identical in both group (69% vs. 68%), however their presence in ≥3 organs was higher in bevacizumab arm at enrolment to the initial phase (57% vs. 47%).

Results of the IMELDA Study

In the maintenance arm, median treatment duration was longer in bevacizumab/capecitabine group (8.3 vs 3.5 months). Adding capecitabine to maintenance bevacizumab provided statistically significant and clinically meaningful improvements in PFS from time of randomisation (HR 0.38, p<0.001; median 11.9 vs 4.3 months) and exploratory analysis (PFS from start of first-line therapy), as well as improvement in median OS from time of randomisation (HR 0.42, p<0.001; 39 vs 23.3 months), despite the smaller than planned sample size because of early termination of accrual. However, at the time of report there was insufficient duration of OS follow-up with low event rate.

There was a manageable increase in adverse events mainly due to hand-foot syndrome experienced in 33% of patients in bevacizumab/capecitabine arm. Hypertension was recorded in 9% of patients in the combined arm and 3% of patients in the bevacizumab only arm. The rate of proteinuria was same (4%) in both groups. Gastroenteritis occured in 3 patients in the bevacizumab single agent arm.

Dr Hope Rugo, who discussed the study results, said that the IMELDA trial tried to answer the question: does continuing bevacizumab post progression have an impact on outcome? Dr Rugo questioned if bevacizumab is an adequate maintenance therapy after response to first-line chemotherapy. In the study, there was a longer duration of treatment with capecitabine/bevacizumab vs bevacizumab (twice the number of cycles), markedly longer PFS, and the PFS from start of first-line was doubled, OS was significantly longer, but there were also almost double the grade > 3 toxicity (mainly hand-foot syndrome, hypertension, but also thromboembolism). Hand-foot syndrome resulted in discontinuation of capecitabine in 10% of patients.

TANIA: Efficacy and safety of continued or reintroduced bevacizumab after first-line bevacizumab for HER2-negative locally recurrent/metastatic breast cancer

The most frequently chosen second-line chemotherapy was capecitabine, 59.7% in chemotherapy group and 60.4% in the chemotherapy plus bevacizumab group.

Median follow-up was similar in both groups. At data cut-off on 20 December 2013, median second-line PFS was 4.2 months in chemotherapy vs 6.3 months in chemotherapy/bevacizumab groups (stratified HR = 0.75, p = 0.0068). Subgroup analysis for PFS by stratification factor was also more favourable for the bevacizumab/chemotherapy grooup.

The best objective response ratewas not statistically different in two groups (16.8% vs 20.9%). However, the stable disease was recorded in 33.5% patients in the chemotherapy arm and 48.9% in the bevacizumab/chemotherapy arm.

The rate of side effects was slighlty higher in the chemotherapy/bevacizumab arm:

hypertension (7.1% vs 13.5%),

proteinuria (0.4% vs 6.9%),

venous thromboembolic event (2.1% vs 3.3%),

febrile neutropaenia (1.7% vs 3.3%),

congestive heart failure (0.4% vs 2.0%),

bleeding (1.7% vs 0.4%),

arterial thromboembolic event (1.3% vs 0%),

wound-healing complication (0% vs 0.8%),

gastrointestinal perforation (0% vs 0.4%),

and fistula/abscess (0% in both groups).

Conclusions of the TANIA Study

The authors concluded that the primary objective of the study was met, showing statistically significantly improved PFS with bevacizumab after disease progression on first-line bevacizumab-containing therapy. Second-line safety results were as expected from previous bevacizumab trials in locally recurrent/metastatic breast cancer. Final OS, PFS from randomisation to third-line progression/death and third-line safety results are anticipated in mid 2015.

Dr Hope Rugo, who discussed the results from this study as well, said that the TANIA trial tried to see the impact of chemotherapy vs targeted therapy alone as maintenance therapy after response. Almost 85% of patients received first-line taxane (73% paclitaxel). There was an unusually long PFS in first-line. Almost 60% received second-line capecitabine. The PFS increased with continued bevacizumab; there was an increase in stable disease but not ORR and, as in prior studies, the greater benefit was in triple-negative breast cancer. Furthermore, there was more toxicity with bevacizumab (hypertension, proteinuria, neutropenia).

Maintenance chemotherapy improves PFS and OS after response to first-line chemotherapy. Unclear additional benefit from bevacizumab must be balanced against cost and toxicity. Bevacizumab alone should not be used as maintenance therapy in this setting. Almost 75% had hormone receptor-positive disease and there might be a role of maintenance hormone therapy.

Dr Rugo concluded that at present the role of bevacizumab is unclear in breast cancer.

Note

Upon the presentation at ESMO 2014, the study results of both IMELDA and TANIA trials are published in the Lancet Oncology.